Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Celgene Corporation
Thalidomide is an immunomodulatory agent with a spectrum of activity that is only partly characterized. Originally introduced as a nonbarbiturate hypnotic, it was used to treat morning sickness, but numerous instances of severe birth defects led to its withdrawal from the market. Thalidomide has been reintroduced and used for a number of immunological and inflammatory disorders, as well as multiple myeloma and other types of cancer. Thalidomide displays anti-angiogenic and immunosuppressive activity. It modulates various cytokines, including inhibiting release of tumor necrosis factor-alpha (TNFα) from monocytes.
Preclinical data suggests that chronic thalidomide treatment reduces amyloid pathology and gliosis in APP23 transgenic mice by way of inhibiting expression of the Aβ-generating secretase enzyme BACE1 (see He et al., 2013). This followed prior studies reporting preclinical efficacy of thalidomide in AD mouse models (e.g. Gabbita et al., 2012; Alkam et al., 2008; Greig et al., 2004; see also further reading). This literature prompted interest in a clinical evaluation of thalidomide in Alzheimer's disease.
In March 2010, the Banner Sun Health Research Institute in Sun City, Arizona, began a 24-week trial of the effect of thalidomide and placebo on CSF and plasma biomarkers, including BACE1, in patients with mild to moderate Alzheimer's disease. As of summer 2013, 25 patients had been randomized; more than 120 potential participants refused participation. The trial was completed in 2013, and results are published (Decourt et al., 2017). More than half of the 25 participants left the trial early due to adverse events. Those who stayed in the study never reached the target dose of 400 mg/day because of side effects. There was one death in the treatment group. At the doses tolerated, cognition neither improved nor deteriorated.
Previously, an open-label Phase 2 had reported no change in biomarkers of inflammation, but significant side effects, in people with amyotrophic lateral sclerosis (Stommel et al., 2009).
A related compound is currently being evaluated in Alzheimer's disease (see lenalidomide).
Clinical Trial Timeline
- Phase 2/3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Banner Sun Health Research Institute||NCT01094340||
Last Updated: 23 Apr 2021
Research Models Citations
- Decourt B, Drumm-Gurnee D, Wilson J, Jacobson S, Belden C, Sirrel S, Ahmadi M, Shill H, Powell J, Walker A, Gonzales A, Macias M, Sabbagh MN. Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial. Curr Alzheimer Res. 2017;14(4):403-411. PubMed.
- Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Channon Smith JY, Harris BT. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):393-404. PubMed.
- He P, Cheng X, Staufenbiel M, Li R, Shen Y. Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of β-secretase in a mouse model of Alzheimer's disease. PLoS One. 2013;8(2):e55091. Epub 2013 Feb 6 PubMed.
- Gabbita SP, Srivastava MK, Eslami P, Johnson MF, Kobritz NK, Tweedie D, Greig NH, Zemlan FP, Sharma SP, Harris-White ME. Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease. J Neuroinflammation. 2012 May 25;9:99. PubMed.
- Alkam T, Nitta A, Mizoguchi H, Saito K, Seshima M, Itoh A, Yamada K, Nabeshima T. Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice. Behav Brain Res. 2008 May 16;189(1):100-6. Epub 2007 Dec 27 PubMed.
- Greig NH, Giordano T, Zhu X, Yu QS, Perry TA, Holloway HW, Brossi A, Rogers JT, Sambamurti K, Lahiri DK. Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp (Wars). 2004;64(1):1-9. PubMed.
- Elçioğlu H, Kabasakal L, Alan S, Salva E, Tufan F, Karan M. Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats. Biotech Histochem. 2013 May;88(3-4):145-52. Epub 2012 Dec 17 PubMed.
- Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, Luo W, Li Y, Caracciolo L, Russo I, Barlati S, Ray B, Lahiri DK, Bosetti F, Greig NH, Rosi S. Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. J Neuroinflammation. 2012 May 29;9:106. PubMed.
- De Filippis D, Cipriano M, Esposito G, Scuderi C, Steardo L, Iuvone T. Are anti-angiogenic drugs useful in neurodegenerative disorders?. CNS Neurol Disord Drug Targets. 2010 Dec;9(6):807-12. PubMed.
- Ryu JK, McLarnon JG. Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brain. Neurobiol Dis. 2008 Feb;29(2):254-66. Epub 2007 Sep 15 PubMed.